The increasing incidence of obesity in the US and other industrialized countries represents a major health problem: Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain forms of cancer, among other diseases. Recently, the elucidation of a number of neuroendocrine mediators of appetite and metabolic control and the identification of the lesions in rodent single gene obesity syndromes have enabled the study of obesity at a detailed molecular level. The hormone leptin is produced in adipose tissue and regulates energy balance by controlling feeding and energy expenditure. Leptin also plays a critical role in regulating the endocrine response to body energy balance. The LRb isoform of the leptin receptor (LR) is highly expressed in hypothalamic nuclei known to regulate body energy balance and endocrine function and mediates important leptin responses. At least two tyrosine residues on murine LRb become phosphorylated and mediate distinct intracellular signals during leptin stimulation. We have generated mutant LRb isoforms (LRbmut) defective by the substitution of single tyrosine residues that fail to mediate the specific intracellular signals. In order to understand how the individual signals initiated by the LRb act to control physiology, we are expressing these LRbmut in mice from the homologously targeted LR gene. Thus, the LRbmut should be expressed at the same levels in the same tissues as wild type LRb, facilitating physiologic studies. This proposal, entitled "Role of leptin receptor signaling pathways in mammalian physiology," seeks to understand the role of the specific signaling pathways regulated by the LRb in the control of physiology. We will first characterize the expression and signaling of (LRbmut) in intact animals and then investigate the regulation of energy balance, glucose homeostasis, and endocrine and neuroendocrine function in these mice. The information these studies yield will bridge the critical gap in our knowledge that lies between the basic biochemistry of leptin signaling and the control of critical physiologic processes by leptin. Furthermore, the understanding gained about the connection between specific cellular signals and physiology will aid in the identification of potential therapeutic targets.